Global research hotspots and frontiers of myasthenia gravis from 2002 to 2021: A bibliometric study

The objective of this study is to utilize bibliometric and visual analysis techniques to identify hotspots and frontiers of research in myasthenia gravis (MG) and provide valuable references for future research. The Web of Science Core Collection (WoSCC) database was used to retrieve literature data related to MG research, which was then analyzed using VOSviewer 1.6.18, CiteSpace 6.1.R3, and the Online Platform for Bibliometric Analysis. The analysis revealed 6734 publications distributed across 1612 journals and contributed by as many as 24,024 authors affiliated with 4708 institutions across 107 countries/regions. The number of annual publications and citations for MG research has steadily increased over the past 2 decades, with the last 2 years alone witnessing a remarkable increase in annual publications and citations to over 600 and 17,000, respectively. In terms of productivity, the United States emerged as the top producing country, while the University of Oxford ranked first in terms of research institutions. Vincent A was identified as the top contributor in terms of publications and citations. Muscle & Nerve and Neurology ranked first in publications and citations respectively, with clinical neurology and neurosciences among the main subject categories explored. The study also identified pathogenesis, eculizumab, thymic epithelial cells, immune checkpoint inhibitors, thymectomy, MuSK antibodies, risk, diagnosis, and management as the current hot research topics in MG, while burst keywords like quality of life, immune-related adverse events (irAEs), rituximab, safety, nivolumab, cancer, and classification indicated the frontiers of MG research. This study effectively identifies the hotspots and frontiers of MG research, and offers valuable references for researchers interested in this area.


Introduction
Myasthenia gravis (MG) is an acquired autoimmune disease involving the neuromuscular junction (NMJ) mainly mediated by antibodies to acetylcholine receptors (AChR). [1][2][3][4] In addition, antibodies against muscle specific tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and ryanodine receptor may also be involved in MG pathogenesis by interfering with AChR aggregation, affecting AChR function and NMJ signaling. [5][6][7] The typical clinical presentation of MG includes fluctuating muscle weakness and fatigue, worsened by activity and improved with rest, which can cause respiratory distress, myasthenic crisis, and, in severe cases, be life-threatening. [8][9][10][11] Epidemiological studies have estimated the global prevalence of MG to be approximately 15 to 25 cases per 100,000 population, with an annual incidence rate of 8 to 10 cases per 1 million. [12] The disease has a bimodal incidence pattern, affecting individuals of all ages but with a higher incidence among young women and elderly men. [13][14][15][16] While the pathogenesis of MG remains unclear, [17,18] available therapies for the condition include cholinesterase inhibitors, glucocorticoids, immunosuppressants, intravenous immunoglobulins, plasma exchange, and thymectomy. [19][20][21][22] Emerging treatment options for MG include hematopoietic stem cell transplantation and targeted biologics, such as eculizumab and rituximab, which diversified the available treatment portfolio for MG patients. [23] Medicine Bibliometrics allows exploration of the knowledge base, research hotspots, and frontiers of a particular field of study through quantitative and statistical analysis of the literature in that field. [24][25][26][27] The technique presents the resulting knowledge structure through visualization, often being referred to as a "scientific knowledge map." [28] Compared to traditional literature reviews, bibliometrics can provide an objective and comprehensive overview for revealing emerging frontiers and providing recommendations for future research and decision-making. [29] Traditional reviews relying on meta or subjective selection often result in limited research inclusion. [30] Despite witnessing a steady increase in the number of publications on MG, to our knowledge, there have been no previous bibliometric analyses reported on this topic. Thus, we conducted the first bibliometric analysis of research on MG using the software programs VOSviewer 1.6.18, CiteSpace 6.1.R3, and the Online Bibliometric Analysis Platform (https://bibliometric.com/). Displaying vast amounts of literature data on a series of knowledge maps, our study offers clear insights on the knowledge base, hotspots, and frontiers of MG research.

Data source and retrieval strategy
The literature records were retrieved and extracted on September 22, 2022, to ensure accurate inclusion and avoid any potential deviations resulting from updates to the Web of Science Core Collection (WoSCC) database. To enhance the accuracy of our retrieval, we combined subject headings with free words for the retrieval strategy, which followed the pattern: (((TS = (MG OR ocular MG OR generalized MG OR MuSK MG)) AND DT = (Article OR Review)) AND LA = (English)) AND DOP = (2002-01-01/2021-12-31). Of the initial 7071 documents retrieved, irrelevant studies, including processing papers (306), early access (16), book chapters (12), retracted publications (2), and those written in non-English languages (1), were excluded. Ultimately, 6734 papers were included, encompassing 5453 articles and 1281 reviews. The literature screening process is illustrated in Figure 1.

Bibliometric analysis
To conduct our analysis, all literature records were exported from the WoSCC database in plain text format and named "download_xxx.txt." These files were then imported into CiteSpace 6.1.R3 software for the analysis of keywords clustering and burst, category co-occurrence and burst, author co-citation, references co-citation, timeline and burst, and journal dual-map overlay. The resulting data were imported into VOSviewer 1.6.18 and Scimago Graphica 1.0.24 software for further analysis, focusing on keywords co-occurrence, country/ region, institution, author collaboration, country/region geographical distribution, and journal co-citation. Additionally, all literature records were exported in UTF-8 format and uploaded to the Online Bibliometric Analysis Platform for country/region collaboration analysis. The CiteSpace software was parameterized as follows: the time span was set from January 2002 to December 2021; Years Per Slice was set to 2; Node Types included keyword, category, cited author, and reference; Selection Criteria was set to top 50 each slice; Pruning included pathfinder, pruning sliced networks, and pruning the merged network with the remaining settings left as defaults. For the VOSviewer software, the following parameter settings were utilized: Normalization method was set to association strength; the minimum thresholds for the number of publications from countries/regions, institutions, and authors were set to 5, 40, and 30 respectively; the minimum threshold for the number of journal citations was set to 1200, while the minimum threshold for the frequency of keyword occurrence was set to 100.

Annual publications and citations
This study included 6734 papers, comprising 5453 articles and 1281 reviews. Figure 2A displays the evolution of publications and citations over the past 2 decades, revealing an overall steady increase in annual publications and citations, indicating ongoing interest and investment in MG research. Notably, the past 2 years have seen annual publications reach over 600 and citation frequency exceeding 17,000, indicating a particularly enthusiastic and productive period in MG research. Figure 2B depicts the annual papers trend of the top 10 countries/regions contributing to the total number of publications, revealing the United States as a prominent contributor to the MG research field, consistently leading in both total and annual documents, with an upward trend in annual papers, albeit with some annual fluctuations.
China, as the second most productive country in MG research, has undergone 3 distinct periods of research. During the first period from 2002 to 2008, relatively few studies on MG were conducted, with an average of <10 papers published annually. The second period from 2009 to 2012 saw the development of MG research to a certain extent, with the average annual number of publications reaching over 20, and by 2012, China surpassed Italy, England, Germany, and France to rank third in terms of annual documents. The third period, from 2013 to 2021, has seen China research in MG advance rapidly, with the annual number of publications growing considerably, surpassing Japan to rank second in 2013 and exceeding 100 publications per year by 2020. China now ranks second after the United States in terms of both total and annual papers. It is noteworthy that since 2020, the combined annual publications of the United States and China have surpassed the combined annual publications of countries/regions ranked third to tenth in total publications, indicating that both countries have become leaders in MG research.

Analysis of nations/regions and organizations
These papers were published by 4708 organizations located in 107 countries or regions. The United States had the highest number of documents (1869, 27.76%), followed by China (847, 12.58%), and Japan (652, 9.68%) ( Table 1). The United States ranked first in total citations, H-index, and total link strength, indicating that it is the leading contributor to MG research with significant academic influence and considerable cooperation with other countries or regions. Despite ranking tenth in total papers, the Netherlands ranked first in the average citations per paper, highlighting the high quality of Dutch research in the field of MG and its broad citation by many scholars.
The time overlay map of countries/regions cooperation network (Fig. 3A) displays countries/regions with no <5 publications. The figure illustrates that research on MG began earlier in developed countries/regions such as the United States, Japan, Italy, England, and Germany, and a substantial amount of research was published in the early stages. On the other hand, China, as a developing country, started later but has significantly advanced in MG research, and an increasing number of papers have been published in recent  Table 1 The top 10 countries/regions in the number of publications.

Rank
Countries  years, making it the main researcher after the United States. Figure 3B provides a more intuitive view of the cooperation between countries/regions, indicating that the United States has established partnerships with multiple countries/regions, while China has limited cooperation with other countries/ regions. Figure 3C clearly shows the intensity of cooperation between the main research countries/regions, revealing active partnerships between the United States and countries/ regions such as England, Germany, China, Canada, and Japan. Although China ranks second in total publications, its total citations, average citations per study, H-index, and total link strength are all at a disadvantage, indicating lower research quality in MG, insufficient academic influence, and less cooperation. Thus, there is a need to strengthen international communication and cooperation to enhance research quality and academic influence, ensuring that the quality and quantity of research are equally important. The time overlay map of the institutional collaboration network (Fig. 4B) displays institutions with at least 40 publications. The University of Oxford was the most productive institution (159, 2.36%), followed by Mayo Clinic (103, 1.53%), and Duke University (98, 1.46%) ( Table 2). The University of  Table 2 The top 10 institutions in the number of publications.

Rank
Institutions  Table 3 The top 10 productive journals.  Hospital in Norway have the closest cooperation, and these 2 institutions have also established extensive collaboration with other institutions. Additionally, the cooperation between the University of Patras and Hellenic Pasteur Institute in Greece is the most frequent. Through the analysis of the cooperation between the 4 institutions in the 2 countries, it can be observed that inter-institutional international cooperation, especially between different countries, needs to be emphasized to promote the high-quality development of MG.

Analysis of journals
These included papers were published in 1612 journals. Muscle & Nerve was the most productive journal (321, 4.77%), followed by Journal of Neuroimmunology (232, 3.45%), and Neuromuscular Disorders (121, 1.80%) ( Table 3). Neurology was the highest-rated journal in terms of average citations per study, H-index, and impact factor (IF), and was also the most frequently cited journal, indicating its high academic standing and quality in the field of MG research. The average H-index and IF of the 10 most productive journals were 123.7 and 5.664, respectively. Forty percent of these journals belonged to Q1, and 50% to Q2, demonstrating that most academic papers on MG are published in high-quality journals. Furthermore, these ten highly productive journals, all from western countries, have made significant contributions to the development of MG and have been widely recognized by scholars.
The journal co-citation network knowledge map (Fig. 5) displays journals that have been cited at least 1200 times. Neurology was the journal cited most frequently (n = 13,629), followed The average H-index and IF of the ten most cited journals were 344 and 24.969, respectively, with 70% in Q1 and 20% in Q2, indicating that high-quality journals are frequently cited. The New England Journal of Medicine had the highest H-index and IF, denoting its recognition as a premier high-quality journal in the academic community with high academic influence. American journals accounted for 80% of the top 10 cited journals, signifying their high academic influence and broad attention and citations. Consequently, priority should be given to reviewing literature from journals with high citation and productivity within this research field.

Analysis of authors
The 6734 publications were authored by 24,024 authors. The time overlay map of the authors collaboration network (Fig. 6A) presents authors with no fewer than 30 papers. Vincent A has produced the most papers (112, 1.66%), followed by Berrihaknin S (78, 1.16%), and Evoli A (78, 1.16%) ( Table 5). Among them, Vincent A from the University of Oxford in the UK was the most productive, cited, and had the highest H-index, indicating that he is a key contributor with a strong academic reputation in the field of MG research. One of his studies provided a comprehensive and systematic exposition of MG from epidemiology, clinical features, pathophysiology, diagnosis, and treatment, thereby laying a theoretical foundation for later research. [31] Vincent A has active collaborations with Marx A, Gilhus NE, Berrih-aknin S, Evoli A, Mantegazza R, and Kaminski HJ. Sanders DB from Duke University ranked seventh in total publications but topped the list in average citations per paper. He was also a highly cited author, with high betweenness centrality, indicating his high academic level and that his high-quality publications have been widely recognized and cited by scholars, leading to significant academic influence in the MG research field. It is noteworthy that 90% of the top 10 authors in the publication are from Europe or North America, while China, the second-highest ranked country, has no top-ranked, highly productive authors.
The author co-citation network knowledge map (Fig. 6B) displays authors whose citations are not <200 times. Vincent A was the most frequently cited author (1136), followed by Jaretzki A (1008), Sanders DB (908) (Table 6). Hoch W from the University of Table 4 The top 10 co-cited journals in terms of citation frequency.

Rank
Co

Analysis of cited references
The knowledge graph of the co-cited literature network (Fig. 7A) reveals papers that have been cited at least 150 times. The top 10 highly cited documents are presented in Table 7. The journals that published these 10 papers had an average IF and H-index of 45.715 and 382.9, respectively, with 90% in Q1 and 10% in Q2, indicating that these papers are high-level studies published in top-quality journals and are the fundamental knowledge base of the MG research field. The highest cited study was published in Neurology by Jaretzki A et al [32] in 2000, proposing a classification system and definitions of treatment response. The second highest cited paper was published in Nature Medicine in 2001 by Hoch W et al, [33] demonstrating that MuSK antibodies are involved in the pathogenesis of AChR antibody seronegative MG (SNMG). The third highest cited paper was published in 1994 by Drachman DB et al [34] in the New England Journal of Medicine, systematically describing MG from clinical features, the NMJ, the acetylcholine receptor, immunopathogenesis, antibody-mediated mechanisms, role of lymphocytes, origin of the autoimmune response, diagnosis, and treatment. The Lancet Neurology published the fourth most cited literature by Meriggioli MN et al [35] in 2009, outlining the epidemiology, immunopathogenesis, clinical presentation, diagnosis, and treatment of MG, including emerging treatment strategies. The fifth-ranked highly cited paper was published by Gilhus NE et al [36] in the Lancet Neurology in 2015, providing an insightful review that systematically described the subgroup classification and treatment strategies for MG. The sixth most cited article was included in Brain by Evoli A et al [37] in 2003, which described the clinical features associated with the presence of anti-MuSK antibodies in a series of patients with SNMG. The seventh highest cited paper was published in Neurology in 1976 by Lindstrom JM et al, [38] analyzing the correlation between antibody titers and clinical parameters of MG and the value of antibody determinations as a diagnostic test for MG. The eighth-ranked study was a review published by Conti-Fine BM et al [39] in 2006 in the Journal of Clinical Investigation, analyzing MG from a historical perspective, pathogenesis, diagnosis, therapeutic management, and future treatment strategies. The ninth ranked paper was an MG international formal consensus providing guidelines for clinicians, released by Sanders DB et al [40] in Neurology in 2016. The tenth highest cited document was published in Muscle & Nerve by Grob D et al [41] in 2008, analyzing the historical development of MG diagnosis and treatment and the effects of age, gender, thymectomy, and the presence of AChR antibodies on the clinical course of MG. The analysis of these 10 highly cited papers reveals that classification, pathogenesis, clinical features, diagnosis, and treatment are vital components of MG research. Table 8 lists the top 10 references for betweenness centrality, which had an average IF and H-index of 19.448 and 253.2, respectively, and 90% of them were in Q1 and 10% in Q2, highlighting their high-quality and pivotal bridging role in the field. Through analysis, it can be observed that 3 studies demonstrated the role of LRP4 antibodies in the pathogenesis of AChR antibodies SNMG [42][43][44] while 5 studies indicated that MuSK antibodies are involved in the pathogenesis of AChR antibodies SNMG. [33,[44][45][46][47] Two studies explored the efficacy of azathioprine and mycophenolate mofetil in the treatment of MG, respectively, [48,49] while 1 publication analyzed the effects of thymus on the pathogenesis of different MG subtypes. [50] Overall, the pathogenesis, therapy, MuSK antibodies, LRP4 antibodies, and thymus represent the research hotspots of MG to some extent. Furthermore, the timeline map of co-cited literature can visually exhibit the time span and transitions of the literature in each cluster by clustering the references, exploring the time evolution of research hotspots in this field. [51] Figure 7B demonstrates that the references of MG research are separated into 15 clusters, with #12 eculizumab, #14 rituximab, and #15 thymic epithelial cells representing the current research hotspots.

References with citation burst
Citation burst refers to literature that is frequently cited within a short period, reflecting the research frontier and emerging trends. [52] The top 30 references for burst strength were identified by adjusting the burst duration to 3 years (Fig. 8). Among them, 9 references with the burst time ending in 2021 are further discussed as they represent the trend of MG research. The reference with the highest burst strength was a review systematically Table 5 The top 10 authors in the number of publications.

Rank
Author  Table 6 The top 10 co-cited authors in citation frequency and betweenness centrality.   Table 7 The top 10 co-cited references in citation frequency.  [36] in Lancet Neurology in 2015. The second-ranked burst study was published by Sanders DB et al [40] in Neurology in 2016, an MG international formal consensus providing guidelines for clinicians. In 2016, The New England Journal of Medicine published the third-ranked paper by Gilhus NE, [12] which analyzed MG from clinical and pathogenic variants, coexisting disorders, therapy, and future directions. The fourth-ranked study in terms of burst strength was published by Wolfe GI et al [53] in the New England Journal of Medicine in 2016, confirming that thymectomy improved the 3-year clinical prognosis of patients with non-thymomatous MG. The publication ranked fifth in burst intensity was included in Nature Reviews Neurology by Gilhus NE et al [54] in 2006, discussing the antibodies involved in the pathogenesis of MG. The sixth highest burst strength literature, published by Berrih-aknin S et al [55] in the Journal of Autoimmunity in 2014, reviewed the latest concepts related to the pathophysiology of Table 8 The top 10 co-cited references for betweenness centrality.  The seventh highest burst strength study, published by Tandan R et al [56] in Muscle & Nerve in 2017, showed that rituximab is a safe and effective treatment for MG, particularly for MuSK antibody-positive patients. The eighth highest burst strength research published in the European Journal of Cancer by Makarious D et al [57] in 2017, stressed the importance of early identification and aggressive treatment of immune checkpoint inhibitor-related toxicities. Finally, the ninth study ranking in burst strength was published in the European Journal of Cancer by Zimmer L et al [58] in 2016, which reported that anti-programmed cell death 1 antibodies could induce immune-related adverse events (irAEs). Analysis of these studies shows that understanding the pathogenesis, subtype classification, thymectomy, antibody assays, rituximab, toxicity of immune checkpoint inhibitors, and irAEs are major frontiers in MG research.

Analysis of subject categories
The knowledge map of category co-occurrence network visualizes the subject categories that appear at least 100 times (Fig. 9).  Table 9 The top 10 subject categories in frequency and betweenness centrality.

Analysis of keywords
Keywords constitute the essence of the research topic and content of a paper, and analyzing their co-occurrence is helpful in exploring the research hotspots in the field. [59][60][61] The keyword co-occurrence time overlay map illustrates keywords with a frequency of occurrence of no <100 times (Fig. 11A). It reveals that MG is the primary research topic, and the topics of MuSK, rituximab, immunology, treatment, risk, management, cancer, diagnosis, and classification have emerged recently, implying that they represent recent research hotspots. Figure 11B presents the keyword clustering analysis map indicating the 10 clustering labels determined by using the log likelihood radio algorithm. As a result, #0 intravenous immunoglobulin, #1 immune checkpoint inhibitors, #2 autoimmune disease, #3 acetylcholine receptor antibody, #4 experimental autoimmune MG, #5 SNMG, #6 MG, #7 multiple sclerosis, #8 NMJ, and #9 thymoma represent the primary research topics in MG. The top 40 high-frequency keywords are listed in Table 10, reflecting the main research content of MG. [62] Moreover, the top 30 keywords with burst intensity were identified by adjusting the burst duration to 3 years (Fig. 12), with the burst time of 7 keywords ending in 2021, indicating that the quality of life, adverse events, rituximab, safety, nivolumab, cancer, and classification currently represent the latest MG research frontier. Through keyword co-occurrence, clustering, and burst analysis, the main research topics of MG were identified, and the research hotspots and frontier trends in recent years were explored.

Analysis of treatment recommendations
Although MG is a NMJ disease caused by autoimmune factors, skeletal muscles are primarily affected. Therefore, in addition to interventions targeting the underlying causes of the disease, it is essential to focus on improving skeletal muscle function during treatment. As a type of motor tissue, skeletal muscle can be effectively improved through appropriate exercise, which is an intervention that contributes to preventing and treating MG. Regular exercise helps to increase muscle strength, [63] enhance neurological function, [64] promote better sleep quality, [65] all of which are important factors in treating MG. Additionally, exercise can help maintain a healthy weight and reduce the risk of other health conditions that may aggravate MG symptoms. However, it is crucial to exercise with caution, and consult with a physician or physical therapist to develop a safe and effective exercise plan tailored to individual needs and limitations. Under appropriate guidance, exercise can become a valuable tool for treating MG.

Strengths and limitations
This study provides a comprehensive, systematic, and intuitive presentation of the knowledge framework and research status of MG research in the last 2 decades, using scientometric analysis. The study also explores the hotspots and frontiers of MG research through the analysis of highly cited literature, highly betweenness centrality literature, reference burst, and keyword co-occurrence, clustering, and burst. To our knowledge, this study represents the first bibliometric analysis of relevant literature in the field of MG. However, our research has some limitations. Firstly, we used data solely from the WoSCC database, which may have led to the exclusion of some relevant studies. Nevertheless, the WoS database is commonly employed for bibliometric studies. [66][67][68] Secondly, we included only articles and reviews in English to ensure accurate software analysis. Finally, as new and relevant papers continue to emerge, recent high-quality research may be underestimated. [69]

Conclusions
Bibliometric research has revealed that the annual number of publications and citations in MG research has displayed an overall upward trend over the past 2 decades, with the annual number of publications and citations exceeding 600 and 17,000, respectively, since 2020. The United States was identified as the major contributor and most influential country in the field of MG research. The University of Oxford was the leading research institution with high academic standing. Vincent A from the University of Oxford was found to be the most published and cited author, with significant academic influence and outstanding contributions. Muscle & Nerve and Neurology respectively were the most published and cited journals. Clinical Neurology and Neurosciences were the main subject categories studied. The hot research topics in recent years include pathogenesis, eculizumab, thymic epithelial cells, immune checkpoint inhibitors, thymectomy, MuSK antibodies, risk, diagnosis, and management. The burst keywords quality of life, irAEs, rituximab, safety, nivolumab, cancer, and classification indicate the current research frontiers in MG.